A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as Adjuvant Treatment for Women With Early-Stage Breast Cancer at High Risk of Recurrence (D-CARE)

Inclusion Criteria:

- Histologically confirmed, AJCC stage II or III breast cancer

- High risk of breast cancer recurrence, defined as documented evidence of one or more
of the following criteria: i) Biopsy evidence of breast cancer in regional lymph
node(s) LN (node- positive disease) Nodal micrometastases only are not considered
node positive ii) Tumor size > 5cm (T3) or locally advanced disease (T4)

- Documented pathological evaluation of the breast cancer for hormone receptor
(estrogen receptor [ER] and progesterone receptor [PR]) status and HER-2 status

- Subjects must be receiving or be scheduled to receive standard of care systemic
adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted
therapy

- For subjects receiving adjuvant therapy only, subjects must have undergone complete
resection of the primary tumor with clean surgical margins, or subjects must have
undergone resection of the primary tumor and be scheduled for further treatment of
the primary tumor with curative intent.

Definitive treatment must be planned to be completed within approximately 9 months of
randomization

- For subjects receiving adjuvant therapy only, time between definitive surgery and
randomization must be ≤ 12 weeks. Definitive surgery may include secondary
interventions (e.g. to clear inadequate surgical margins)

- For subjects receiving adjuvant therapy only, subjects with node positive disease
must have undergone treatment of axillary LN with curative intent, or subjects must
be scheduled for further treatment of regional lymph nodes with curative intent.
Definitive treatment must be planned to be completed within approximately 9 months of
randomization

- For subjects receiving adjuvant therapy only, subjects must not have received prior
neoadjuvant treatment. Endocrine treatment for less than 30 days prior to surgery is
not considered prior neoadjuvant treatment

- For subjects receiving neoadjuvant therapy only, time between start of neoadjuvant
treatment and randomization must be ≤ 8 weeks

- For subjects receiving neoadjuvant therapy only, subjects must be scheduled to
undergo definitive treatment (including surgery and/or radiotherapy) with curative
intent within approximately 9 months of starting neoadjuvant treatment

- Female subjects with age ≥ 18 years

- Subjects with reproductive potential must have a negative pregnancy test within 14
days before randomization

- Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9
mmol/L (11.5 mg/dL)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

- Prior or current evidence of any metastatic involvement of any distant site

- History of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular
carcinoma in situ [LCIS]) prior to the current diagnosis

- Osteoporosis requiring treatment at the time of randomization or treatment considered
likely to become necessary within the subsequent six months

- Any prior or synchronous malignancy (other than breast cancer), except i) Malignancy
treated with curative intent and with no evidence of disease for ≥ 5 years prior to
enrollment and considered to be at low risk for recurrence by the treating physician
ii) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Active infection with Hepatitis B virus or Hepatitis C virus

- Known infection with human immunodeficiency virus (HIV)

- Prior history or current evidence of osteomyelitis/osteonecrosis of the jaw

- Active dental or jaw condition which requires oral surgery

- Planned invasive dental procedure for the course of the study

- Non-healed dental or oral surgery

- Use of oral bisphosphonates within the past 1 year

- Prior or current IV bisphosphonate administration

- Prior administration of denosumab

- Subject currently is enrolled in or has not yet completed at least 30 days since
ending other investigational device or investigational drug study(s), or subject is
receiving other investigational agent(s)

- Subject is pregnant or breast feeding, or planning to become pregnant within 7 months
after the end of treatment.

- Subject is of child bearing potential and is not willing to use, in combination with
her partner, 2 highly effective methods of contraception or abstinence during
treatment and for 7 months after the end of treatment

- Subject has known sensitivity to any of the products to be administered during the
study (e.g., mammalian derived products, calcium, or vitamin D)

- Subject has any kind of disorder that compromises the ability of the subject to give
written informed consent and/or to comply with study procedures.

- Any major medical or psychiatric disorder that may prevent the subject from
completing the study or interfere with the interpretation of the study results